Methotrexate1plasma concentrations were measured repeatedly over 48 hours after each of 5 subsequent intrathecal injections in 14 children and 8 adult patients with acute lymphoblastic leukaemia. Two patterns of concentration profiles were distinguished:a) The plasma concentration reached a rather low maximum, followed by a relatively slow decline (‘slow type’):b) The plasma concentration increased rapidly to a relatively high value after which it declined rather steeply (‘fast type’).The incidence of the ‘fast type’ increased progressively with the number of intrathecal injections.When the plasma concentration-time curves were described by a pharmacokinetic 2-compartment open model with first-order absorption, it was calculated that the transfer of methotrexate from the spinal fluid into the plasma is much slower for the ‘slow type’ compared with the ‘fast type’.Assuming concentration-dependent cytostatic activity, the therapeutic efficacy in the central nervous system is likely to be less for the ‘fast type’ than for the ‘slow type’. Systemic toxicity resulting from the ‘slow type’ is expected to be higher than from the ‘fast type’.